Quinolines Conrad-Limpach synthesis

A few extensions of the Conrad-Limpach synthesis have been applied to the synthesis of 4,7-phenanthrolines. Unlike o-phenylenediamine, which gives a quinoxaline derivative, p-phenylenediamine reacts with excess of ethyl ethoxalylpropionate to give an intermediate bisanil, which cyclizes in hot diphenyl ether to afford 3,8-dicarboethoxy-l,10-dihydroxy-2,9-dimethyl-4,7-phenanthroline in high yield.237 With diethyl ethoxymethylenemalonate as condensing agent, 6-amino-8-methoxy-quinoline has been converted into 2-carboethoxy-l-hydroxy-6-methoxy-4,7-phenanthroline.238 A related condensation affording 1-... 

A modification of the known Conrad-Limpach synthesis of quinolines, using anilino-methylenemalonates instead of / -anilinocrotonates, has long been known290,291. 

This sequence calls to mind an old, long-known reaction the thermal version of the Conrad-Limpach synthesis of quinoline-4-one derivatives by thermolysis of aryl-aminocrotonates110a arylaminomethylenemalonates1 lob c arylaminomethylene-cyanoacetates110d and related compounds111-114. ... 

A modification of the known Conrad-Limpach synthesis of quinolines, using anilino-methylenemalonates instead of j -anilinocrotonates, has long been known ° N-Aryl and N-heteroaryl derivatives of aminomethylene malonates are also very useful and fruitful synthons for formation of 4-aminoquinolines used as antimalarials (equation 215), of the anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates and of antibacterial nalidixic acid derivatives (equation 216). Each of these is an important group of pharmaceuticals, developed in the last twenty years. Because of its medicinal interest this route is widely used for synthesis of quinolines and pyridinofused heterocycles. The chemistry has been comprehensively reviewed in a recent monograph . Hence, no further details are given here. 

Synthetic pharmaceuticals based on the quinoline ring are numerous. During World War II when supplies of the highly important antimalarial quinine became scarce, research was conducted in many laboratories to find a synthetic substitute. From this research came the dmg chloro-quine (9.103) and many related highly active compounds. Chloroquine is still in use today in the treatment of malarial infections. It is synthesized by a modification of the Conrad-Limpach synthesis as shown in Scheme 9.52. 

Alternatively, several new methods were unfolded which eventirally became conventional for synthesizing the structural core of quinoline. These are (a) Combes synthesis using anilines and p-diketones (b) Conrad-Limpach synthesis employing anilines and P-ketoesters (c) Doebner-Miller reaction involving anilines and a,P-unsatmated carbonyl compotmds (d) Friedlander synthesis using 2-amino-benzaldehyde and acetaldehyde (e) Povarov reaction which involves reaction of an aniline, a benzaldehyde and an activated alkene also known as Aza-Diels-Al-... 

Conrad-Limpach-Knorr synthesis, of quinolines, 21 189 Conrad recycling process, 21 455 Conradson carbon test method, 11 705, 721 Consensus materials standards, 15 743 Consent decree protocols, in the United States, 11 692-694 Consent decrees, 11 689-690 Consequence analysis, 21 860-861 Consequence modeling, 13 165-166 Conservation applications, high performance fibers in, 13 398 Conservation of energy, 21 290 Conservation of mass, 11 737, 738-739 Conservation, of resources, 24 164-167 Conservation scientists, 11 398-399 Consistent force field, 16 744 Consolidants, in fine art examination/ conservation, 11 410... 

A very large group of syntheses in which the /3,y-bond is formed are those in which a side chain electrophile attacks the benzene ring. These include the Skraup and Doebner-von Miller syntheses (dealt with in Section 2.08.2.2.3(ii)), the Knorr, Conrad-Limpach and Combes syntheses of quinolines (dealt with here), the Pomerantz-Fritsch synthesis of isoquinolines, and many syntheses of phenanthridines and of acridines. 

There have been some further examples of the use of the Conrad-Limpach reaction on substituted 5-aminoquinolines for the synthesis of 4-hydroxy-1,7-phenanthrolines, although the products (see Section IV,F,1) should properly be designated as phenanthrolinones.169 Hot diphenyl ether is often employed as the medium for ring closure.170 Ethyl trifluoro-acetoacetate has been used successfully in place of ethyl aceto-acetate, and this variation has allowed entry to 2-trifluoromethyl-substituted 1,7-phenanthrolines.96 Extensions of the Conrad-Limpach type of synthesis starting with m-phenylenediamine (20) and utilizing diethyl ethoxymethylene malonate or ethyl ethoxalylacetate, reagents frequently used in quinoline syntheses, have afforded, after hydrolysis,... 

Conrad-Limpach-Knorr Synthesis. When a /1-kcto ester is the carbonyl component of these pathways, two products are possible. Aniline reacts with ethyl acetoacetate below IOO"C to form 3-anilinocrotonate, which is converted to 4-hydroxy-2-methylquinoline by placing it in a preheated environment at 250°C. If die initial reaction lakes place at 160 C, acetoacetanilide forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoltne. This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents. 

The synthesis of 1,8-naphthyridines using adaptations of quinoline syntheses (Knorr, Conrad-Limpach, Combs, Chichibabin, Doebner, and Doebner-Miller) has been discussed by Hauser and Weiss104 and the reader is referred to this work for details. 

The formation of quinolines and benzoquinolines by the condensation of primary aryl amines with P-diketones followed by an acid catalyzed ring closure of the Schiff base intermediate is known as the Combes quinoline synthesis. The closely related reaction of primary aryl amines with p-ketoesters followed by the cyclization of the Schiff base intermediate is called the Conrad-Limpach reaction and it gives 4-hydroxyquinolines as products. ... 

The lower temperature variation of this reaction initially forms an imine or an enamine. Friedel Crafts cyclization gives the 4-hydroxyquinoline in what is called the Conrad-Limpach reaction. xhis reaction generally gives the opposite regioisomeric product to that obtained by the Knorr quinoline synthesis. The initially formed product is usually the enamine (as in the formation of 248 from aniline and ethyl acetoacetate). 3 Under acidic conditions the iminium salt is formed and cyclized with the aromatic ring. A more efficient method simply heated 248 to 250°C in mineral oil, giving a 90% yield of 249. A variety of other functional groups can be tolerated in the molecule when this procedure is used. 

Some applications of the described reactions include the preparation of chloroquine, an important anti-malarial, which is made by reacting 4,7-dichloroquinoline with 4-diethylamino-l-methylbutylamine at 180 °C. 7-Chloro-4-hydroxyquinoline, a precursor of 4,7-dichloroquinoline, was routinely prepared by heating 3-chloroaniline with the ethyl ester of formylacetic acid, through the Conrad-Limpach quinoline synthesis. ... 

This reaction is related to the Camps Reaction, Conrad-Limpach Quinoline Synthesis, Doebner-Miller Reaction, Gould-Jacobs Quinoline Synthesis, Niementowski Reaction, and Skraup Reaction. 

Other references related to the Conrad-Limpach quinoline synthesis are cited in the literature. 

The reaction is related to the Combes Quinoline Synthesis and Conrad-Limpach Quinoline Synthesis. 

This reaction was first reported by Knorr in 1886. It is the synthesis of 2-hydroxyquinolines via the cyclization and dehydration of an anilide intermediate condensed from )0-ketoesters and anilines at a relatively high temperature. Right after this report, Conrad and Limpach also reported a similar reaction between anilines and )0-ketoesters but at low temperatures, which resulted in the formation of 4-hydroxy quinolines from the intermediate of alkyl crotonate. Thus this reaction is known as the Knorr synthesis, Knorr-Limpach method, Knorr cyclization, Conrad-Limpach-Knorr reaction, or Knorr quinoline synthesis. It has been reported that the formation of an alkyl crotonate intermediate is favored at moderate or low temperature in the presence of iodine or an acid catalyst, whereas intermediate anilide is formed at high temperatures. ... 

The last two decades of the 19th century proved to be an important era for the development of quinoline chemistry. It was during this time period that various methods for synthesizing quinolines, such as the Friedlander quinoline synthesis, Pfitzinger quinoline synthesis, Doebner-Miller quinoline synthesis, Conrad-Limpach quinoline synthesis, Combes quinoline synthesis, and Camps quinoline synthesis were first reported. In 1882, Friedlander showed that the condensation of 2-aminobenzaldehyde (4) with acetaldehyde (5) provided quinoline (6). ... 

The Simonis chromone synthesis and the Pechmann-Duisberg reaction can be considered as O-analogs of the Conrad-Limpach and Knorr reactions for the preparation of quinolines from the corresponding aniline. ... 

G. E. Gream, A. K. Serelis, Aust. J. Chem. 31, 863 (1978). Cf. Combes Quinoline Synthesis Conrad-Limpach Reaction. 

Skraup and Conrad-Limpach reactions to appropriate benzo[6]thiophen derivatives. Substitution reactions of thieno[3,2-/]quinoline (559), which was prepared by a Skraup synthesis from 5-aminobenzo[6]thiophen, have been studied. The same method has also been used earlier for the synthesis of the 7- and 9-methyl derivatives of (559). Nitration, bromina-tion, and acylation of (559) occur in the 2-position. Some reactions of... 

An intramolecular ketene electrocyclization also seems to occur in the Conrad-Limpach quinoline synthesis. In the heating of the 6-anilinocrotonic acid ester in a high-boiUng solvent at 240-250 °C, the ketene 466 is generated, which undergoes inttamolecular cy-clization to form a quinoline derivative 467 ... 

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